mRNA Vaccine Protects against Zika Virus

Zika virus (ZIKV), a mosquito-borne flavivirus, has recently triggered global concern due to severe health complications. In 2015, a large ZIKV outbreak occurred in the Americas and established a link between ZIKV and microcephaly in newborn babies, spontaneous abortion, persistent viremia, and Guillain–Barré syndrome. While antivirals are being developed and prevention strategies focus on vector control, a safe and effective Zika vaccine remains unavailable. Messenger RNA (mRNA) vaccine technology has arisen as a flexible, simplified, and fast vaccine production platform. Here, we report on an mRNA vaccine candidate that encodes the pre-membrane and envelope (prM–E) glycoproteins of ZIKV strain Brazil SPH2015 and is encapsulated in lipid nanoparticles (LNPs). Our ZIKV prM–E mRNA-LNP vaccine candidate induced antibody responses that protected in AG129 mice deficient in interferon (IFN) alpha/beta/gamma (IFN-α/β/γ) receptors. Notably, a single administration of ZIKV prM–E mRNA-LNP protected against a lethal dose of ZIKV, while a two-dose strategy induced strong protective immunity. E-specific double-positive IFN-γ and TNF-α T-cells were induced in BALB/c mice after immunizations with a two-dose strategy. With the success of mRNA vaccine technology in facing the coronavirus (COVID-19) pandemic, our data support the development of prM–E RNActive® as a promising mRNA vaccine against Zika to counter future epidemics.

Public health impact of delaying second dose of BNT162b2 or mRNA-1273 covid-19 vaccine: simulation agent based modeling study

ObjectiveTo estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination.DesignSimulation agent based modeling study.SettingSimulated population based on real world US county.ParticipantsThe simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions.InterventionsSimulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated.Main outcome measuresCumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days.ResultsOver all simulation replications, the median cumulative mortality per 100 000 for standard dosing versus delayed second dose was 226 v 179, 233 v 207, and 235 v 236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested.ConclusionsA delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.

Modeling the use of SARS-CoV-2 vaccination to safely relax non-pharmaceutical interventions

In response to the COVID-19 pandemic, widespread non-pharmaceutical interventions (NPIs), including physical distancing, mask wearing, and enhanced hygiene, have been implemented. As of March 2021, three effective vaccines have been approved for emergency use in the United States, with several other vaccines in the pipeline. We use a transmission model to study when and how NPIs could be relaxed in the United States with relative safety as vaccination becomes more widespread. We compare different relaxation scenarios where NPIs begin to relax 0-9 months after vaccination begins for both a one dose and two dose strategy, with historical levels of social interactions being reached within 1 month to 1 year. In our model, vaccination can allow widespread relaxation of NPIs to begin safely within 2 to 9 months, greatly reducing deaths and peak health system burden compared to relaxing NPIs without vaccination. Vaccinated individuals can safely begin to relax NPIs sooner than unvaccinated individuals. The extent of delay needed to safely reopen depends primarily on the rate of vaccine rollout, with the degree of protection against asymptomatic infection playing a secondary role. If a vaccination rate of 3 million doses/day can be achieved, similar to the typical rollout speed of seasonal influenza vaccination, NPIs could begin to be safely relaxed in 2-3 months. With a vaccination rate of 1 million doses/day, a 6–9-month delay is needed. A one dose strategy is preferred if relative efficacy is similar to a two-dose series, but the relative benefit of this strategy is minimal when vaccine rollout is fast. Due to the urgent need to pursue strategies that enable safe relaxation of NPIs, we recommend a two-dose strategy with an initial delay of at least 3 months in relaxing restrictions further, and that the speed of vaccine rollout be given immediate priority.

Comparing Vaccination Strategies in Canada Under Different Assumptions

ABSTRACTThis paper estimates the outcomes of two different COVID-19 vaccination strategies in Canada for the mRNA vaccines currently approved for Emergency Use Authorization (EUA), modelled on the vaccination and effectiveness of the Pfizer vaccine which is likely to be more widely administered in Canada. The first strategy is the manufacturer recommended standard of two doses (two-dose strategy) given within 21 days apart versus a strategy of giving a larger group a single dose of vaccine (first-dose-for-most strategy) by delaying the second injection.Three parameters are varied in the course of 36 estimation scenarios of the population-level effects of the two vaccination strategies. The first is the effectiveness of a single dose of vaccine at preventing disease, the second is the effectiveness of the vaccine at preventing transmission of the virus, and the third is the rate of transmission of the virus during the course of the simulations.Over the course of the different scenarios, the first-dose-for-most strategy was superior in reducing disease transmission in all scenarios where vaccination is assumed to have an effect on viral transmission. The results for fatalities was mixed, with the first-dose-for-most strategy being superior in cases where a higher first-dose effectiveness at preventing disease was assumed.Finally, in the best-guess scenarios where a 75% reduction in disease transmission and a 92.6% effectiveness at preventing disease from a single dose were used, the first-dose-for-most strategy was superior in a situation with reduced vaccine doses available, and switching to the first-dose-for-most strategy earlier helped to prevent a higher proportion of cases and deaths.

A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD

BackgroundExposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure—while reducing the need for red blood cell transfusions—is unknown.MethodsIn this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 µg/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician.ResultsThere were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 µg) compared with the titration-dose group (53.6 µg median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) µg and 53.6 (31.1, 89.9) µg, respectively; the median of the difference between treatment groups was −22.1 (95% CI, −26.1 to −18.1) µg.ConclusionsThese findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

P1371HEART FAILURE HOSPITALISATIONS IN THE PIVOTAL TRIAL OF IV IRON IN HAEMODIALYSIS PATIENTS: A PRE-SPECIFIED SECONDARY ANALYSIS

Background and Aims Heart failure (HF) is a common and potentially deadly complication in patients receiving haemodialysis which is difficult to diagnose and treat. The impact of a proactive high-dose strategy compared to a reactive low-dose strategy of IV iron administration was investigated in the PIVOTAL randomised trial in incident haemodialysis patients, with fatal HF and HF hospitalisation being components of the composite primary cardiovascular endpoint as well as a pre-specified key secondary event. The aim of this analysis was to examine the effect of a proactive high-dose strategy compared to a reactive lower dose strategy on HF events in patients recruited to PIVOTAL. Method As with the primary composite cardiovascular endpoint, HF hospitalisations in PIVOTAL were recorded prospectively via an electronic database, and events were then adjudicated by a blinded Endpoint Adjudication Committee. The time-to-event analyses of the primary, secondary and post hoc outcomes were performed in the intention-to-treat population using Cox proportional hazards regression, with treatment group as the only explanatory variable. The Kaplan–Meier method was used to estimate event rates. Both fatal and non-fatal HF events were analysed as time to first event, and a recurrent event analysis was also performed for non-fatal events. Results Overall, 2141 participants were followed for a median of 2.1 years. A first fatal or non-fatal HF event occurred in 51 of 1093 patients (4.7%) in the high-dose iron group and in 70 of 1048 patients (6.7%) in the low-dose iron group (hazard ratio 0.66, 95% confidence interval 0.46 to 0.94; P<0.001) (Figure). There was a total of 63 HF events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose iron group, giving a rate ratio of 0.59 (0.40-0.87); p=0.0084. A history of HF and diabetes were independent predictors of a heart failure event. Conclusion Compared with a low-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in incident patients undergoing haemodialysis, with large relative and absolute risk reductions.

Comparison of Low- Versus High-Dose Four-Factor Prothrombin Complex Concentrate (4F-PCC) for Factor Xa Inhibitor–Associated Bleeding: A Retrospective Study

Background: Although andexanet alfa was recently approved as a specific reversal agent for apixaban and rivaroxaban, some providers still elect to administer 4-factor prothrombin complex concentrate (4F-PCC) instead, due to concerns surrounding efficacy, thrombotic risk, administration logistics, availability, and cost. Previous studies have described success with 4F-PCC doses ranging from 25 to 35 U/kg, with some guidelines recommending 50 U/kg. Objectives: The purpose of this study was to compare hemostasis between patients receiving low- (20-34 U/kg) versus high-dose (35-50 U/kg) 4F-PCC for the urgent reversal of apixaban and rivaroxaban. Patients/Methods: We performed a retrospective cohort study at a level one trauma center and comprehensive stroke center between January 2015 and December 2018. Main exclusion criteria included patients receiving less than 20 U/kg or if postreversal imaging were unavailable. Outcomes assessed included hemostasis for critical bleeding associated with apixaban or rivaroxaban and postoperative bleeding for reversal for emergent procedures. Results: The low-dose strategy was administered to n = 57 (57.6%) patients at a mean dose of 26.6 U/kg. The high-dose strategy was used in n = 42 (42.4%) patients at a mean dose of 47.6 U/kg. There was no difference in hemostasis by dosing strategy (75.4% vs 78.6%, P = .715) or hospital mortality (19.3% vs 35.7%, P = .067). No difference was found for secondary end points, including thrombotic events (5.3% vs 2.4%, P = .635) and hospital length of stay (11.3 vs 12.5 days, P = .070). Conclusions: Our comparison addresses a gap in the literature surrounding optimal dosing and supports a similar efficacy profile between dosing low- versus high-dose treatment.